Synthesis and antileukemic activities of C1-C10-modified parthenolide analogues

Aaron M Kempema; John C Widen; Joseph K Hexum; Timothy E Andrews; Dan Wang; Susan K Rathe; Frederick A Meece; Klara E Noble; Zohar Sachs; David A Largaespada; Daniel A Harki

doi:10.1016/j.bmc.2015.05.037

Synthesis and antileukemic activities of C1-C10-modified parthenolide analogues

Bioorg Med Chem. 2015 Aug 1;23(15):4737-4745. doi: 10.1016/j.bmc.2015.05.037. Epub 2015 May 30.

Authors

Affiliations

¹ Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
² Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
³ Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
⁴ Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
⁵ Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: daharki@umn.edu.

Abstract

Parthenolide (PTL) is a sesquiterpene lactone natural product with anti-proliferative activity to cancer cells. Selective eradication of leukemic stem cells (LSCs) over healthy hematopoietic stem cells (HSCs) by PTL has been demonstrated in previous studies, which suggests PTL and related molecules may be useful for targeting LSCs. Eradication of LSCs is required for curative therapy. Chemical optimizations of PTL to improve potency and pharmacokinetic parameters have focused largely on the α-methylene-γ-butyrolactone, which is essential for activity. Conversely, we evaluated modifications to the C1-C10 olefin and benchmarked new inhibitors to PTL with respect to inhibitory potency across a panel of cancer cell lines, ability to target drug-resistant acute myeloid leukemia (AML) cells, efficacy for inhibiting clonal growth of AML cells, toxicity to healthy bone marrow cells, and efficiency for promoting intracellular reactive oxygen species (ROS) levels. Cyclopropane 4 was found to possess less toxicity to healthy bone marrow cells, enhanced potency for the induction of cellular ROS, and similar broad-spectrum anti-proliferative activity to cancer cells in comparison to PTL.

Keywords: Acute myeloid leukemia; Bone marrow toxicity; Cyclopropanation; Parthenolide; Sesquiterpene lactone.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alkenes / chemistry
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Bone Marrow Cells / cytology
Bone Marrow Cells / drug effects
Bone Marrow Cells / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Crystallography, X-Ray
Drug Design
Drug Screening Assays, Antitumor
Humans
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / mortality
Mice
Molecular Conformation
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism
Reactive Oxygen Species / metabolism
Sesquiterpenes / chemical synthesis
Sesquiterpenes / chemistry*
Sesquiterpenes / pharmacology

Substances

Alkenes
Antineoplastic Agents
Reactive Oxygen Species
Sesquiterpenes
parthenolide

Abstract

Publication types

MeSH terms

Substances

Grants and funding